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How the inflammatory response is regulated during these processes is undefined. Pyroptosis is an inflammatory form of cell death mediated by gasdermin D (GSDMD). Through in vivo, cultured epithelial cells and organoids, it is shown that pyroptosis occurs in epithelial cells at the implantation site. Compared with those on day 4 of pseudopregnancy and delayed implantation, pyroptosis\u2010related protein levels are significantly increased on day 4 of pregnancy and activated implantation, suggesting that blastocysts are involved in regulating pyroptosis. Blastocyst\u2010derived cathepsin B (CTSB) is stimulated by preimplantation estradiol\u201017\u03b2 and induces pyroptosis in epithelial cells. Pyroptosis\u2010induced IL\u201018 secretion from epithelial cells activates a disintegrin and metalloprotease 12 (ADAM12) to process the epiregulin precursor into mature epiregulin. Epiregulin (EREG) enhances in vitro decidualization in mice. Pyroptosis\u2010related proteins are detected in the mid\u2010secretory human endometrium and are elevated in the recurrent implantation failure endometrium. Lipopolysaccharide treatment in pregnant mice causes implantation failure and increases pyroptosis\u2010related protein levels. Therefore, the data suggest that modest pyroptosis is beneficial for embryo implantation and decidualization. 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